MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors

Abstract

Mitochondrial Ca²⁺ homeostasis loses its control in many diseases and might provide therapeutic targets. Mitochondrial Ca²⁺ uptake is mediated by the uniporter channel (mtCU), formed by MCU and is regulated by the Ca²⁺-sensing gatekeeper, MICU1, which shows tissue-specific stoichiometry. An important gap in knowledge is the molecular mechanism of the mtCU activators and inhibitors. We report that all pharmacological activators of the mtCU (spermine, kaempferol, SB202190) act in a MICU1-dependent manner, likely by binding to MICU1 and preventing MICU1's gatekeeping activity. These agents also sensitized the mtCU to inhibition by Ru265 and enhanced the Mn²⁺-induced cytotoxicity as previously seen with MICU1 deletion. Thus, MCU gating by MICU1 is the target of mtCU agonists and is a barrier for inhibitors like RuRed/Ru360/Ru265. The varying MICU1:MCU ratios result in different outcomes for both mtCU agonists and antagonists in different tissues, which is relevant for both pre-clinical research and therapeutic efforts.

Keywords: MCU; MICU1; Ru265; SB202190; calcium; kaempferol; ruthenium red; spermine.